Peripheral nerve degeneration due to disease or trauma can result in serious disability from permanent weakness, numbness or chronic pain. A better understanding of the cellular and molecular mechanisms of peripheral axon regeneration and reinnervation may lead to improved treatment strategies. This proposal describes a method to transect individual axons and directly observe the cellular dynamics of peripheral target reinnervation in vivo, using zebrafish trigeminal neurons as a model. This technique was used to quantitatively characterize wildtype regeneration at several developmental stages. The overall objective of the proposed research is to define the cellular and molecular mechanisms involved in reinnervation of peripheral targets. The characterization of reinnervation in wildtype animals will serve as a baseline to compare the effects of various zebrafish mutants and pharmacological treatments. This work may identify novel molecular targets that can be exploited for therapeutic purposes in peripheral neuropathy in humans. The specific goals of the project are outlined below. Aim 1) To investigate intracellular signaling in individual injured axons by specifically determining when, where, and how the Rho pathway acts to mediate inhibition of reinnervation. Aim 2) To identify extrinsic factors that modulate the capacity for reinnervation using zebrafish mutants and pharmacological manipulations. This aim specifically focuses on the role of phagocytic cells, peripheral glia, the extra cellular matrix components, and the inflammatory response.